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Nuclear Transcription Factor Kappa B Downregulation Reduces Chemoresistance in Bone Marrow-derived Cells Through
Brenda Loaiza1, Salomon Hernández-Gutierrez2, Juan Jose Montesinos3
1Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Background And Aims:
Nuclear transcription factor kappa B (NF-κB) is associated with many types of refractory cancer. However, despite multiple strategies to treat cancer and novel target drugs, multidrug resistance still causes relapses. The best-characterized mechanism responsible for multidrug resistance involves the expression of the MDR-1 gene product, P-glycoprotein (P-gp). Because the direct inhibition of this protein is very toxic, other methods of multidrug resistance (MDR) regulation have been proposed. The MDR-1 promoter sequence contains a κB site, which is recognized by NF-κB. The aim of this work was to characterize whether NF-κB modulation changes the response of bone marrow-derived cells (BMDCs) to chemotherapy.
Results:
We exposed BMDCs to etoposide and doxorubicin, two of the most used antineoplastic drugs. BMDCs presented high tolerance to these drugs, which correlated with high intrinsic P-gp activity and strong protein expression of NF-κB. To determine the mechanism behind the poor sensitivity of BMDCs to chemotherapy, we blocked the activity of the heterodimer protein NF-κB using the pharmacological inhibitor Bay 11-7085 and through the transfection of an adenovirus negative mutant of I kappa B alpha. The multidrug resistance phenotype of BMDCs was reversed by inhibiting the NF-κB pathway, and this change was accompanied by a decrease in P-gp activity.
Conclusions:
NF-κB is a possible target for improving the antineoplastic response.
Insights
Nuclear transcription factor kappa B (NF-κB) drives multidrug resistance in cancer. Inhibiting NF-κB in bone marrow cells reversed chemotherapy resistance by reducing P-glycoprotein (P-gp) activity.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Nuclear transcription factor kappa B (NF-κB) is implicated in various refractory cancers.
- Multidrug resistance (MDR), often mediated by P-glycoprotein (P-gp) via the MDR-1 gene, contributes to cancer relapse.
- Direct P-gp inhibition is toxic, necessitating alternative MDR regulation strategies.
Purpose of the Study:
- To investigate if modulating NF-κB impacts the chemotherapy response of bone marrow-derived cells (BMDCs).
- To explore the role of NF-κB in the MDR phenotype of BMDCs.
Main Methods:
- BMDCs were exposed to etoposide and doxorubicin.
- NF-κB activity was inhibited using Bay 11-7085 and a dominant-negative IκBα adenovirus.
- P-gp activity and expression were assessed.
Main Results:
- BMDCs exhibited high tolerance to chemotherapy, correlating with high P-gp activity and NF-κB expression.
- Inhibition of the NF-κB pathway reversed the MDR phenotype in BMDCs.
- Reversal of MDR was associated with decreased P-gp activity.
Conclusions:
- NF-κB pathway inhibition can overcome chemotherapy resistance in bone marrow cells.
- Targeting NF-κB represents a potential strategy to enhance antineoplastic treatment efficacy.
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